Sirtuins and Autophagy in Age-Associated Neurodegenerative Diseases: Lessons from the C. elegans Model
Abstract
:1. Introduction
2. Neurodegeneration
2.1. Alzheimer’s Disease
2.2. Parkinson’s Disease
3. Autophagy: Friend or Foe
4. C. elegans: A Model for Research
5. Sirtuins: Master Regulators
6. Sirtuins and Neurodegeneration
7. Sirtuins and Regulation of Autophagy in Neurodegenerative Diseases
8. Concluding Remarks
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
HDAC | Histone Deacetylase |
WHO | World Health Organization |
Aβ | Beta-Amyloid |
NFTs | Neurofibrillary Tangles |
APP | Amyloid Precursor Protein |
AD | Alzheimer’s Disease |
DMTs | Disease Modifying Therapeutics |
PD | Parkinson’s Disease |
SNCA | Synuclein Alpha |
PINK1 | PTEN-induced Putative Kinase 1 |
PARKN | Parkin |
DJ-1 | Protein Deglycase |
LRRK2 | Leucine-Rich Repeat Kinase 2 |
LAMPs | Lysosome-Associated Membrane Proteins |
LC3 | Light Chain 3 |
PAS | Phagophore-Associated Site |
YFP | Yellow fluorescent protein |
GFP | Green fluorescent protein |
LGG-1 | LC3, GABARAP and GATE-16 family |
AMP | Adenosine Monophosphate |
ATP | Adenosine Triphosphate |
AMPK | AMP-Activated Protein Kinase |
mTORC | Mammalian Target of Rapamycin Complex |
ULK1/2 | UNC-51-like Autophagy-Activating Kinase 1/2 |
ATG | Autophagy-Related |
RNA | Ribonucleic Acid |
FOXO | Forkhead Box transcription factor |
HLH | Helix-Loop-Helix |
DAF-16 | Abnormal DAuer Formation-16 |
TFEB | Transcription Factor EB |
Akt | A Serine/Threonine Protein Kinase |
PI3K | Phosphoinositide 3-Kinase |
VATPase | Vacuolar ATPase |
SIRT | Sirtuin |
cAMP | Cyclic Adenosine Monophosphate |
IRE1α | Inositol-requiring kinase 1α |
PERK | Protein kinase (PKR)-like Endoplasmic |
Reticulum Kinase | |
ATF6 | Activating Transcription Factor 6 |
CAT | Catalase |
TLR | Toll-like Receptor |
HIF-1 | Hypoxia-Inducible Factor 1 |
NAD | Nicotinamide Adenine Dinucleotide |
SOD | Superoxide Dismutase |
ROS | Reactive Oxygen Species |
PPARγ | Peroxisome Proliferator-Activated Receptor |
Gamma | |
PGC-1α | PPARγ Coactivator-1α |
MPTP | 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine |
TβRI | TGF-β Receptor Protein 1 |
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S. No. | Pathways Regulating Autophagy | Regulatory Molecules | |
---|---|---|---|
Mammals | C. elegans | ||
1. | Nutrient/energy sensing pathway | mTORC1, Ras-cAMP-PKA, AMPK [61] | let-363, AMPK |
2. | Insulin/growth factor signaling pathway | PKB/Akt, Ras-MAPK | DAF-2, Ras-MAPK |
3. | Stress response pathway | IRE1α, PERK, ATF6α [62], ATG7, ATG8, SOD, CAT [63], HIF-1 | ire-1, pek-1, atf-6 [64], atg7, lgg-1, sod-3, ctl-1/2 |
4. | Pathogen-induced regulation | TLRs | TOL-1 [65] |
5. | Transcriptional regulation and chromatin modification | FOXO, HDAC 1,2,3 (SIRT1-7) and 6 [66] | DAF-16, HDA-1 [66], sir-2.1, sir-2.2, sir-2.3, sir-2.4 |
S. No. | Human Sirtuin | Location | C. elegans Homolog | Enzymatic Activity | Function |
---|---|---|---|---|---|
1. | SIRT1 | Nucleus (shuttles between nucleus and cytoplasm) [71] | sir-2.1 | Deacetylase activity | Transcription regulation, cell survival chromatin organization, development and differentiation, stress responses, metabolism regulation, neuroprotection, adult neurogenesis, synaptic plasticity, cognition, emotion, circadian rhythm, microglial activation [72]. |
2. | SIRT2 | Mainly cytoplasmic but can translocate to the nucleus as well | Deacetylase activity | DNA repair, cell cycle, mitosis, transcription regulation, adult neurogenesis, microglial activation, neuroprotection, regulation of emotions [72]. | |
3. | SIRT3 | Mitochondria [73] | Strong deacetylase activity | Mitochondrial functioning, metabolism regulation, ATP production, reducing oxidative stress, sleep-wake patterning, regulation of age-related hearing loss [72]. | |
4. | SIRT4 | Mitochondria | sir-2.2 & sir-2.3 | ADP-ribosyl transferase activity | Mitochondrial functioning, metabolism regulation |
5. | SIRT5 | Mitochondria | Desuccinylase and demalonylase activities; weak deacetylase activity | Fatty acid oxidation, insulin secretion [74] | |
6. | SIRT6 | Nucleus (translocates to cytoplasm under stress) [75] | sir-2.4 | Deacetylase activity, ADP-ribosyl transferase activity | Genome stability, DNA repair, control of circadian rythms, stress response, inflammation |
7. | SIRT7 | Nucleus, specifically in nucleolus | Deacetylase activity | Cell survival, rRNA regulation, cellular stress regulation [76] |
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Naseer, A.; Mir, S.S.; Takacs-Vellai, K.; Nazir, A. Sirtuins and Autophagy in Age-Associated Neurodegenerative Diseases: Lessons from the C. elegans Model. Int. J. Mol. Sci. 2021, 22, 12263. https://doi.org/10.3390/ijms222212263
Naseer A, Mir SS, Takacs-Vellai K, Nazir A. Sirtuins and Autophagy in Age-Associated Neurodegenerative Diseases: Lessons from the C. elegans Model. International Journal of Molecular Sciences. 2021; 22(22):12263. https://doi.org/10.3390/ijms222212263
Chicago/Turabian StyleNaseer, Anam, Snober Shabnam Mir, Krisztina Takacs-Vellai, and Aamir Nazir. 2021. "Sirtuins and Autophagy in Age-Associated Neurodegenerative Diseases: Lessons from the C. elegans Model" International Journal of Molecular Sciences 22, no. 22: 12263. https://doi.org/10.3390/ijms222212263